This program project grant (PPG) renewal describes a series of studies from 4 senior investigators. The global objective of this application is to further our understanding of the various mechanisms that are involved in the neurohumoral excitation characteristic of the chronic heart failure (CHF) state. During the previous funding period we have produced evidence that central sympathetic outflow is strongly modulated by the interplay between angiotensin II (Ang II) and nitric oxide (NO). Based on novel preliminary data we now propose that additional central and peripheral mechanisms contribute to the sympatho-excitation in CHF. These include the role of reactive oxygen species (ROS) and the involvement of glutamate receptors and abnormal gamma amino butyric acid (GABA) mechanisms in NO signaling in the hypothalamus. Projects I-III are continuation projects and Project IV is a new project that we believe fits well with the overall theme of this PPG. In Project I we propose that central Ang II mediates increases in sympathetic outflow and baroreflex resetting by virtue of it stimulatory effect on NAD(P)H oxidase and production of superoxide anion. The increase in superoxide anion provides a mechanism for the reduction in NO bioavailability and thus the lack of a central sympatho-inhibitory pathway. We propose that exercise training (EX) ameliorates the sympatho-excitatory CHF state by up regulating scavenging enzymes such as superoxide dismutase (SOD). In Project II, the role of glutamate and GABA in the paraventricular nucleus (PVN) will be investigated in the sympatho-excitation of rats with CHF. The involvement of both Ang II and NO in the processes associated with NR1, AT1 and NMDA receptors will be investigated. The role of EX on the alterations in glutamate and GABA responses will also be examined in this project. Project III continues to investigate the cellular mechanisms that are responsible for augmented arterial chemoreflex function in the CHF state. In this project the role of NO on glomus cell ion channel defects will be investigated in CHF. In addition, the roles of Ang II, NO and reactive oxygen species will be examined in both isolated cells and intact animals. EX will be an additional component of this project. Project IV is a new addition to this PPG. In this project we will examine the role of Ang II, NO and ROS on the role of the cardiac sympathetic afferent reflex in the genesis of sympatho-excitation in CHF. The role of EX on cardiac sympathetic afferent reflex function will also be investigated in this project. All projects will use novel genetic techniques (gene transfer and antisense administration) and state of the art hemodynamic, cellular and molecular techniques to facilitate answers to the questions posed.